: The primary goal of this proposal is the structural basis for the mechanism of action of gamma interferon (IFN-gamma). Particular emphasis will be placed on IFN- gamma/receptor interactions and subsequent event as they relate to signal transduction, with a view toward understanding the mechanism of IFN-gamma regulation of cells. Thus, the investigators will: (1) Determine the crystal structure of a complex between IFN-gamma and the cytoplasmic domain of the alpha chain of the IFN-gamma receptor. These studies are a logical extension of Dr. Johnson's demonstration that IFN- gamma, through its C-terminus (which contains a functional nuclear localization sequence) binds to the cytoplasmic domain of the IFN-gamma receptor alpha chain. (2) Determine the mechanism of nuclear translocation of IFN-gamma, including the identification of structural and residue requirements, interaction with receptor cytoplasmic domain, nuclear transport proteins such as the heteroduplex importin alpha/beta, and the IFN-gamma STATl-alpha transcription factor. (3) Determine the mechanism of nuclear translocation of IFN-gamma receptor alpha chain (IFN-gamma R-alpha), including the identification of structural and residue requirements for interaction with IFN-gamma, STATs, and nuclear transport proteins. (4) Determine if IFN-gamma-R beta chain undergoes endocytosis and nuclear translocation after IFN-gamma binds to receptor complex and the significance of translocation/non-translocation as it relates to signal transduction.